Significance Of the estimated 13 million people worldwide infected with HIV, one million are infants and children. In spite of new and potent antiretrovirals that have been developed, there has been limited progress made in identifying methods for long-term treatment of disease. For gravid women and infants, there continues to be a lag in the development and application of new treatments, thus providing less therapeutic options. Objectives 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) significantly inhibits viral reverse transcription and has been reported to sustain low virus load in SIV-infected rhesus monkey infants. Based on these findings, studies were conducted to assess the safety, efficacy, and placental transfer of PMPA when administered once daily subcutaneously to gravid rhesus monkeys during the second and third trimesters, and their respective offspring (30 mg/kg/day). Results Fetuses (SIV-infected and uninfected) were monitored sonographically, and maternal/fetal blood samples collected at select time points for hematologic, clinical chemical, virologic, immunologic, and pharmacologic assessments. Newborns were delivered by cesarean-section at term, and nursery reared for postnatal studies. Results of these studies have shown (1) significant placental transport of PMPA, with peak fetal drug levels at 1-3 hours post-maternal administration, (2) a significant and sustained reduction in viral load in SIV-infected fetuses and infants, and (3) marked improvements in outcome (survival, growth, health) in SIV-infected offspring. However, decreased infant body weights and alterations of select serum biochemical parameters (decreased phosphorus levels, elevated alkaline phosphatase) have been shown to occur in approximately 67% of PMPA-treated infants, with severe growth restriction and bone-related toxicity in approximately 20-25% of animals studied (SIV-infected, uninfected). These data suggest that although PMPA holds great promise for HIV-infected patients, there is the potential for bone-related toxicity at chronic, high dosages, particularly in young patients. Future Directions Treatment of SIV-infected fetuses and neonates with lower dosages will be explored in order to eliminate the potential for bone-related toxicity. KEYWORDS pregnancy, growth, fetus, infant, PMPA, placental transport, SIV, bone toxiicity; PUBLIC ATIONS:Tarantal, A.F., Marthas, M.L, Bischofberger, N. Administration of (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) to Gravid and Infant Rhesus Macaques (Macaca mulatta) Safety and Efficacy Studies. J. AIDS (submitted).